Side chain degradation of 11-keto steroids



United States Patent SIDE CHAIN DEGRADATION OF ll-KETO STEROIDS DonaldReinhold, New Brunswick, N. J., assignor to Merck & Co., Inc., Rahway,N. 1., a corporation of New Jersey No Drawing. Application June 30,1953, Serial No. 365,225

30 Claims. (Cl. 260-23955) This invention pertains in general to thepreparation of 11,20-diketo-cyclopentanopolyhydrophenanthrene compounds,and more particularly to a novel process for the production of suchcompounds from an ll-keto-cyclopentanopolyhydrophenanthrene compoundhaving an unsaturated steroid side chain.

In the synthesis of cortisone from sterols, such as ergosterol andstigmasterol, the characteristic side chain, which is attached to ring Dof the steroid nucleus and which has the following structural formula:

wherein R is methyl or ethyl, is ordinarily degraded to the two carbonpregnane side chain after the introduction into the steroid nucleus ofthe C-ll ketone substituent. Degradation methods heretofore advocatedhave involved the transformation of the unsaturated ergostene orstigmastene side chain to a bisnorallocholanic acid; reaction of thisacid with a Grigna-rd reagent; dehydration of the resulting carbinol,and oxidation of the consequent 11- keto-bisnorallocholene compound.This type of process necessitated the use of expensive reagents, longreaction times and diflicult isolation procedures.

These objectionable features are substantially avoided by the methodembodying the invention, which can be successfully employed withll-k-eto steroids as starting materials. In this method the double bondof the steroid side chain is ozinized, and the, resulting ozonide isdecomposed under reductive conditions to form a bisnorcholanyl aldehyde,which is then subjected to side chain enol acylation with a suitablereagent and catalyst, after which the enol acylate is ozonized anddecomposed under reductive conditions to yield the desired11,20-diketocyclopentanopolyhydrophenanthrene compound.

An important inventive feature of the improved process is the selectivecharacter of the enol acylation of the side chain in the bisnor aldehydewithout material acylationof the C11 substituent. It has been found thatwhen the catalysts normally employed in the acylation, such as ptoluene'sulfonic acid, methane sulfonic acid and sulfuric acid, are used, theundesired acylation will occur in ring C. This is avoided in accordancewith theinvention, by employing a catalyst in the selective enolacylation of the steroid side chain which has the same acid radical asthe acylation reagent.

The latter reagent is advantageously, an acid anhydride of a lowercarboxylic acid, and the catalyst is an alkali metal salt, preferablythe sodium salt, of the same acid. More specifically, it has been foundadvantageous to employ acetic anhydride as the reagent, and sodiumacetate as the catalyst.

In the process embodying the invention the starting ma- 2,780,621Patented Feb. 5, 1957 teria'l, a A-cyclopentanopolyhydrophenanthrene-1l-one compound, is reacted withozone to produce the correspondingcyclopentanopolyhydrophenanthrene-1Lone-22,- 23-ozonide, which is thendecomposed under reductive conditions to form the correspondingcyclopentanopolyhydrophenanthrene-l1-one-22-al, which may also berefer-red to as a bisnorcholan-l1-one-22-al compound.

This bisnorcholan l1-one-22-al compound is then selectively enolacylated, using a suitable reagent together with a catalyst that has thesame acid radical as the reagent, thereby acylating the C-17 side chainwithout material acylation of the ll-keto substituent, thereby producingthe corresponding enol acylate, the A -pisnorcholene-22- ol-ll-oneacylate compound, and more particularly such an enol acylate having anacyloxy substituent at 0-3 with the same acyl radical as that attachedto the C-17 side chain. When said bisnorcholan-22-al-1l-one compound hasa hydroXy substituent at C-3, this substituent will also be acylatedduring acylation of the aldehyde side chain, with the resultantformation of the corresponding A -bisnorcholene-3,22-diol-l1-one-3,22-diacylate.

The acylated product is ozonized to form the correspondingbisnorchol-an-22-ol-1l-one 20,22-ozonide acylate such asbisnorcholan-3,22-diol-3,22-diol-1l-one 20,22- ozonide acylate. Thelatter ozonide is then decomposed under reductive conditions to form thecorresponding cyclopentanopolyhydrophenanthrene 11,20 dione compound,more particularly, the corresponding pregnancl1,20-dione compound.

The process embodying the invention will now be described more indetail. The starting material, a A 41-keto-cyclopentanopolyhydrophenanthrene co m p o u n d, which may have afunctional substituent at C-3, may be obtained in known manner, asdescribed in I. A. C. S. 73, 2396 (1951). The substituent at C3 may be afree hyd-roxyl group, but preferably is acylated to an acyloxysubstituent, which advantageously is an acetoxy derivative; but otheresters, such as the propionate, butyrate or benzoate, may be used. Moreparticularly, the starting material may be a A -ergostene-11-onecompound, as for example, a A -ergostene-3-ol-ll-one-acylate such as A-ergostene-3-ol-1 l-one alkanoate, A -ergostene 3-01-11- one-acetate, n-ergostene- 3 -ol 11 -one-propionate, A ergostene-3-ol-1 l-one-butyrate,A -ergostene-3-ol-l l-onebenzoate, or A -ergostene-3-ol-11-one, a A-stigmastenell-one compound, as for example, A -stigma-stene-3-olll-oneacylate, such as a A -stigmastene-3ol-1l-onealkanoate, specifically A-stigmastene-3-ol-1l-one-acetate, A -stigmastene-3-ol-1l-one-propionate,A stigmastene-3- ol-l l-one butyrate, A-stigmastene-3-ol-1l-one-benzoate, or A -s-tigmastene-3-ol-1l-one, andthe like.

The process will be described for illustrative purposes as applied tothe production of allopregnane-11,20-dione compounds starting with thecorresponding A -ergostenell-one compound; the reactions involved inthis process may be chemically represented, insofar as the changestaking place in the radicals attached to rings C and D are concerned, asfollows:

Compound 1 Compound 2 onioooyfn onto 00H.

D. Zn 0 Compound 6 Compound The starting material, a A -ergostene-ll-onecompound (compound 1), preferably A -ergostene-3-ol-1lone-acetate isozonized by passing a stream of ozonized oxygen through, a solution ofsaid sterol in an organic solvent at temperatures ranging from about '70C. to aboutroom temperature. Solvents such as methylene chloride,ethylene chloride, acetic acid, ethyl acetate and chloroform may beemployed. For instance, the step has been carried out satisfactorilywith the indicated ergostene derivative in a methylene chloride solutionat about 60 C., and also in an acetic acid solution at about roomtemperature. In all cases, ozone slightly in excess of one molecularequivalent is charged to the reaction solution, preferably between 1.0and 1.2 equivalents being used.

The ergostane-l1-one-22,23-ozonide (compound 2) produced in this manneris decomposed under reductive conditions in such a way as to obtainmaximum yields of the aldehyde, as for example, with zinc and aceticacid, or with sodium iodide and acetone. In the preferred method anylow-boiling solvent is replaced with acetic acid, followed by theaddition of excess zinc dust. The reaction mixture is then stirred atabout room tempera ture for one-half to two hours, the zinc removed byfiltration, and the corresponding ll-keto-bismorallocholan-22-al-11-onecompound (compound3) is isolated by conventional means.

When other starting compounds are used as indicated hereinabove, thedescribed ozonization and reduction will of course produce thecorresponding bisnorallocholan- 22-al-ll-one compounds. These productsare novel; and they constitute, together with the method of producingthem, features of the invention. These bisnorallocholan- 22-al-ll-onecompounds include bisnorallocholan-22-al- 3-ol-11-one acylate,bisnorallocholan-22-al-3-ol-1l-onealkanoate, specificallybisnorallocholan-22-al-3-ol-1l-oneacetate,bisnorallocholan-ZZ-al-3-*ol-l l-one-butyrate,bisnorallocholan-ZZ-al-3-01-ll-one-benzoate andbisnorallocholan-22-al-3-ol-ll-one, and the like.

In the illustrative process, the bisnoralloeholan-ZZ-alll-one compound(compound 3), specifically bisnorallocholan-22-al-3-ol-1l-one-acetate isselectively enol acylated, as by reaction with an acid anhydride,preferably acetic anhydride, in, the presence of a catalyst. In order toavoid the. possibility of ester interchange, nuclear hydroxyl groupsshould be protected with the same acyloxy radicalas that present in thecatalyst that is used to form the enol acylate. Since there are twoenolizable functions, namely the C-1l ketone and the 0-22 carbonylgroup, as already noted, an alkali metal salt of the acid correspondingto the anhydride-reagent is used as the catalyst, acetic anhydride asthe reagent and sodium acetate as the catalyst being preferred; butother lower alkanoic anhydridessuch: aspropionic, butyric and benzoicanhydrides may be. employed as reagents together with the sodiumor'potassium salt of the same acid as catalyst.

When other starting materials already enumerated are employed, theenolacylate thus obtained is the correspending 22 acylate of. the. A-bisnorcholene ll-one compound (compound 4), as for example, a A-bisnorallocholene-3,22 diol l l-one-3,22-diacylate, such as A-bisnorallocholene 3,22- diol 11-one-3,22-dialkanoate, A-bisnorallocholene 3,22-diol-11-one-3,22- dipropionate, A-bisnorallocholene 3,22-diol-1 l-one- 3,22-dibutyrate, A-bisnorallocholene 3,22 diol-l1- one-3,22-dibenzoate, and the like.

The A -l l-keto 22-acyloxy-bisnorallocholene compound (compound 4) whichin the illustrative operation is A -bisnorallocholene3,22-diol-1l-one-3,22-diacylate, is .isolated byrstandard methods, whichmay include removal of the acylating reagent, dissolution in suitablesolvents and crystallization.

The finalstate, including the steps ofv ozonization of the A-bisnorallocholene 22 ol ll-one-22-acylate compound (compound 4) to formthe corresponding bisnorallocholan 22 ol1-1l-one-20,22eozonide-22-acylate (compound 5) and. decomposition of saidozonide is carried out in substantially the: same manner as the firstozonization and decomposition steps previously described. The resultingallopregnane compound (compound 6) is isolated in substantially purecondition, as by extraction with an organic solvent, removal of thesolvent, and recrystallization from a suitable solvent such as methanolor petroleum ether.

The process embodying the invention also results in the production ofnew compounds; and these compounds, as well as the method of producingthem, are features of theinvention. Thesenovel substances includebisnoral- .locholan-22-al-ll-one with a substituent at C3, which morespecifically may be a hydroxy or an acyl-oxy group, such as an acetoxy,propionoxy, butyroxy or benzyloxy radical; also, A-bisnorallocholene-3,22-diol-ll-one- 3,22-diacylate, in which theacyloxy substituent may be a benzoyloxy or an alkanoyloxy radical, suchas an acetoxy, propionoxy or butyroxy radical.

The following specific examples of processes embodying the invention aregiven by way of further illustration and not of limitation.

EXAMPLE 1 Stage 1 A solution of 13.70 g. of A -ergostene-3-ol-1l-one-3-acetate in 600 ml. of methylene chloride in a one-liter Morton flaskis cooled in a Dry Ice-acetone bath to about -60 C. Ozonized oxygen ispassed through the solution at the rate of 0.98 mole perminute forforty-two minutes. The solution is allowed to warm to room temperatureand is then transferred to a one-liter roundbottom flask, equippedxwitha modified Claisen distilling head and a capillary tube, and distilledunder nitrogen to give ergostane-3-ol-lLone-22,23-ozonide-3-acetate.

One hundred milliliters of acid are added to the ozonide andthe-methylene chloride removed under reduced pressure below-30 C.Anadditional ml. of acetic acid are added and the ozonide decomposed bythe addition of zinc dust over a-period of twenty minutes, thetemperature being maintained between 15 C. and 20 C. The mixture isstirred for an additional thirty minutes, filtered, and the zinc dustWashed with 50 ml. of acetic acid. The acetic acid solution isdilutedwith 50 ml. of water and extracted 'with two 300 ml. portions ofether. The ether extracts are'combined and washed withwater until thewashings are neutral. The other solution is then washed with' -two250'ml. portions of 1N sodium hydroxide solution toremove acidicproducts formed during the ozonizationz The ethersolutionis washed againwith water, dried over magnesium sulfate, filtered and ether distilledin vacuo. The crude crystalline product thus obtained is digested with100 ml. of petroleum ether, cooled and filtered to yieldbisnorallocholan-22-al- 3-o1-l1-one-3-acetate melting at 13 1137 C.

Stage 2 A solution of 9.72 g. of said bisnorallocholan-22-al-3-ol-ll-one-3-acetate in 200ml. of acetic anhydride and 3 g. of anhydroussodium acetate is heated under reflux for six hours. The aceticanhydride is then removed by distillation under reduced pressure. Thecrude residue is digested with 50 ml. of 80% aqueous MeOH, cooled,filtered and dried. The A -.bisnorall0cholene-3,22-diol-ll-one-3,22-diacetate obtained in this way is purified byrecrystallization from methanol to give, substantially pure material; M.P. 164-166 C.

Stage 3 A solution of 5.65 g. of said A -bisnorallocholene-3,22-diol-1l-one-3,22-diacetate in 400 ml. of methylene chloride iscooled in a Dry Ice-acetone bath to about 60 C., and ozonized oxygen ispassed through the solution at the rate of 0.93 mole per minute forsixteen minutes. After warming to room temperature, 80 ml. of aceticacid is added and the methylene chloride removed in vacuo below 30 C. togive bisnora1locholane-3,22- diol-l 1-one-20,22-ozonide-3,22-diacetate.

The acetic acid solution of this ozonide is transferred to a threenecked round-bottom flask equipped with a stirrer and thermometer, withan additional 20 ml. of acetic acid. The ozonide is decomposed by adding7 g. of zinc dust over a period of twenty minutes while maintaining thetemperature between C. and C. The mixture is then stirred for anadditional thirty minutes, filtered and the zinc dust washed with 20 ml.of acetic acid. The filtrate is diluted with 500 ml. of ether, and theether extract washed successively with water, 1 N sodium hydroxidesolution and water. After drying the ether solution over magnesiumsulfate and filtering the ether is distilled ofi to obtain a viscous oilwhich partially crystallizes. The product is twice recrystallized fromhot methanol to give allopregnane-3-ol-11,20-dione-3- acetate; M. P.131-132 0; this material forms a yellow 2,4-dinitrophenylhydrazonemelting at 238239 C.

EXAMPLE 2 Stage 1 A solution of 13.7 g. of A -erg0stene-3-ol-11-one-3-acetate in 250 ml. of glacial acetic acid is cooled to 20 C. Ozone ispassed through the solution at the rate of 1.2 moles per minute forthirty minutes, forming the ozonide ergostane 301-11-one-22,23-ozonide-3-acetate. The solution of the ozonide is cooledto 15 C. and 20.0 g. of zinc dust added in small portions, thetemperature being maintained between 15 C. and 24 C. The mixture isstirred for an additional hour, the zinc dust removed by filtration, andthe filtrate poured into 500 ml. of ice water. The resulting precipitateis filtered and dried in a vacuum oven at about 65 C. overnight.

The dry crude product thus obtained is dissolved in ether, the ethersolution washed with ice cold 1 N sodium hydroxide solution andsaturated sodium chloride solution. The ether solution is then driedover magnesium sulfate, filtered, and the ester distilled in vacuo toyield the aldehyde as a viscous oil which crystallizes on standing. Theproduct is chromatographed on 160 g. of acid-washed alumina. Residuesfrom 1:3 petroleum ether-benzene and benzene eluates are combined andrecrystallized from n-hexane to give essentially purebisnorallocholan-22-al-3-o1-1l-one-3-acetate; M. P. 130- 133 C.

Stages 2, 3 and 4 These stages may be carried out as described inExample 1.

. While a preferred form of the invention and a number of variationsthereof have been disclosed, other modifications may be made withoutdeparting from the spirit and scope thereof as defined in the claims.

I claim:

1. The process which comprises ozonizing a A-cyclopentanopolyhydrophenanthrene-1l-one compound having a sterol sidechain, hydrolyzing the resulting ozonide under reducing conditionsthereby producing the corresponding bisnorallocholan-22-al-1l-onecompound, acylating the C-22 aldehyde group of the latter compound withan acylating agent in the presence of an alkali metal salt having thesame acid radical as said acylating agent and acting as a catalyst,thereby forming the corresponding A -bisnorallocholene-11-one-22-ol22-acylate, ozonizing said acylate, and hydrolyzing the resultingozonide under reducing conditions, thereby forming the correspondingallopregnane-1l,20-dione compound.

2. The process which comprises ozonizing a A -ergostene-ll-one compound,hydrolyzing the resulting ozonide under reducing conditions therebyproducing a bisnoralloeholan-ZZ-al-ll-one compound, enol acylating thelatter compound with an anhydn'de of a lower alkanoic acid in thepresence of an alkali metal salt of said acid acting as a catalyst,thereby producing a A bisnorallocholene 11 one 22-ol-22-acylatecompound, ozonizing the latter compound and hydrolyzing the resultingozonide under reducing conditions thereby forming the correspondingallopregnane-ll,20-dione compound.

3. The process which comprises ozonizing a A- stigmastene-l l-onecompound, hydrolyzing the resulting ozonide under reducing conditionsthereby producing a bisnorallocholan-ZZ-ahl l-one compound, enolacylating the latter compound with an anhydride of a lower alkanoic acidin the presence of an alkali metal salt of said acid acting as acatalyst, thereby producing a A bisnorallocholenel l-one-2-2 o1 22acylate compound, ozonizing the latter compound and hydrolyzing theresulting ozonide under reducing conditions thereby forming thecorresponding allopregnane-11,20-dione compound.

4. The process which comprises ozonizing a A -ergostene-3-ol-ll-one-3-acylate compound, hydrolyzing the resulting ozonide underreduced conditions thereby producing the correspondingbisnorallocholan-3-oll-1-one-22- al-3-acylate compound, enol acylatingthe latter compound with an anhydri'de of a lower alkanoic acid in thepresence of an alkali metal salt of said acid acting as a catalyst,thereby producing the corresponding A bisnorallocholene-3,22-diol-1l-one3,22 diacylate compound, ozonizing the latter compound, and hydrolyzingthe resulting ozonide under reducing conditions, thereby forming thecor-responding allopregnane-3-ol-ll,20- dione-3-acylate compound.

5. The process which comprises reacting n -ergostene-3-ol-11-one-3-acet-ate with ozone to form ergostene-3-o'l-l1-one-3-acetate-22,23-ozonide, reacting said ozonide with ahydrolyzing agent under reducing conditions thereby providingbisnorallocholane-3-ol-11-one-22-al- 3-acetate, reacting the lattercompound with acetic anhydride in the presence of sodium acetatecatalyst, thereby forming A -bisnorallocholene-3,22-diol-1l-one-3,22-diacetate, reacting the latter compound with ozone to producebisnorallocholan-3,22-diol-1l-one-3,22-diacetate-20,22, ozonide, andreacting said ozonide with a hydrolyzing agent under reducingconditions, thereby forming allopregnane-3-ol-11,20-dione-3-acetate.

'6. The process which comprises reacting a 22,23- ozonide of a A-cyclopentanopolyhydrophen'anthrene-1lone compound having a sterol sidechain with a hydrolyzing agent under reducing conditions to form thecorresponding cyclopentanopolyhydrophenanthrene-l1- one-22-al compound.

7. The process which comprises reacting an ergostane-11-one-22,23-ozonide compound with a hydrolyzing 7 agent under reducingconditions to form the corresponding bisnora1locholan-22-a1-1l-onecompound.

8. 'The process which comprise reacting a stigmastane l1 one 22,23ozonide compound with a hydrolyzing agent under reducing conditions toform the corresponding 'bisnoral1ocho1an-22-al-1l-one compound.

9. The process which comprises reacting ergos'tane-3-ol-l1-one-3-acetate-22,23-ozonide with a hydrolyzing agent underreducing conditions to produce bisnorallocho1an-3-ol-11-one-22-al-3-acetate.

10. The process which comprises enol acylation of the -22 aldehyde groupof a bisnorallocholan-ZZ-al- 1'1-one compound with an 'acylating agentin the presence of an alkali metal salt having the same acid radical assaid acylating agent and acting as a catalyst, thereby forming thecorresponding A -bisnorallocholene-11- one-22-0l 22-acylate,ozonizingsaid acylate, and hydrolyzing the resulting ozonide underreducing conditions, thereby forming the correspondingallopregnane-11,20- dione compound.

11. The process which comprises enol acyl-ation of the C-22 aldehydegroup of a bisnorallocholan-ZZ-alll-one compound with an anhydride of alower alkanoic acid in the presence of an alkali metal salt of said acidacting as a catalyst, thereby forming the corresponding A-bisnorallocholene-11-one-22-o1 22-acylate, ozonizing said acylate, andhydrolyzing the resulting ozonide under reducing conditions, therebyforming the corresponding a1lopregnane-11,20-dione compound.

12. The process which comprises enol acylation of the C-22 aldehydegroup of a bisnorallocholan-22-al-1lone compound with acetic anhydridein the presence of an alkali metal acetate acting as a catalyst, therebyforming the corresponding A -bisnoral1ocholan-11-one-22- o1 22-acetate,ozonizing said acetate, and hydrolyzing the resulting ozonide underreducing conditions, thereby forming the correspondingallopregnane-11,20-dione compound.

13. The process which comprises enol acylation of the C-22 aldehydegroup of a bisnorallocholan-3-ol-11-one 22-a1 compound with an acylatingagent in the presence of an alkali metal salt having the same acidradical as the reagent and acting as a catalyst, thereby forming thecorresponding A -bisnorallocholan1-3,22-diol-11- one 3,22-diacylate,ozonizing said acylate, and hydrolyzing the resulting ozonide underreducing conditions, thereby forming the correspondingallopregnane-3-o1- 11,20-dione 3-acy1ate compound.

14. The process which comprises reacting a bisnoral-1och-olan-22-al-1l-one compound with an acylating agent in the presenceof an alkali metal salt catalyst having the same acid radical as saidacylating agent, thereby forming the corresponding A-bisnorallocho-lene-11- one-22-ol 22 acylate compound.

15. The process which comprises reacting a bisnorallocholan-22-al-l1-onecompound with an anhydride of a lower alkanoic acid in the presence ofan alkali metal salt of said acid acting as a catalyst, therebyproducing the corresponding A -bisnorallocholan-11-one-22-o122-alk-anoate compound.

16. The process which comprises reactingbisnorallochola-n-3-o1-11-one-22-a1-3-acetate with acetic anhydride inthe presence of sodium acetate catalyst, thereby forming A-bisnora1locholene-3,22-diol-11-one-3,22-diaceta'te.

17. The process which comprises reacting a A bisnorallocholene-l1-0ne-22-o1 22-acylate compound with ozone to form the corresponding A-bisnorallocholan- 11-one-22-ol 22-acylate compound.

18. The process which comprises reacting a N bisnorallocholene-ll-ene-22-ol-22-acylate compound with ozone to produce the correspondingbisnorallocholanel1-one-22-ol-22-acylate20,22-ozonide compound.

19. The process which comprises reacting N-bisnorallocholene-3,22-diol-11-one-3,22-diacetate with ozone to producebisnorallocholan-3,22-dio1-l1-one-3,22-diacetate-20,22-ozonide.

20. Theprocess which comprises reacting a A-bisnorallocholan-l1-one-22-ol 22-acylate with a hydrolyzing agent underreducing conditions to produce the correspondingallopregnane-l1,20-dione compound.

21. The process which comprises reacting abisnorallocholan-l1-one-22-o1-22-acylate-20,22-ozonide with ahydrolyzing agent under reducing conditions to produce the correspondinga1lopregnane-11,20-dione compound.

22. The process which comprises reactingbisnorallocholan-3,22-diol-1Lone-3,22 diacetate 20,22 ozonide with ahydrolyzing agent under reducing conditions to produceallopregnane-3-ol-1 1,20-dione-3-acetate.

23. Bisnorallocholan-3-ol-11-one-22-al-3-(lower alkanoate).

24. Bisnorallocholan-3-ol-11-one-22-al-3-acetate.

25. Bisnorallocholan-3-ol-11-one-22-a1.

26. A -Bisnora1locholene-11-one-22 ol 22-(lower alkanoate).

27. A -Bisnorallocholene-3,22-dio1-11-one-3,22-bis- (lower alkanoate).

28. A -Bisnora1locholene 3,22-dio1-11-one-3,22-diacetate.

29. Bisnorallocholan-3,22-dio1-1I-one 3,22 bis(1oweralkanoate)-20,22-ozonide.

30. Bisnorallocholan 3,22 diol 11 one 3,22 diacetate-20,22-ozonide.

References Cited in the file of this patent UNITED STATES PATENTS2,588,396 Levin Mar. 11, 1952 OTHER REFERENCES Chambcrlin: J. A. C. 5.,73, 2396-97 (1951).

1. THE PROCESS WHICH COMPRISES OZONIZING A$22-CYCLOPENTANONPOLYHYDROPHENANTHRENE-11-ONE COMPOUND HAVING A STEROLSIDE CHAIN, HYDROLYZING THE RESULTING OZONIDE UNDER REDUCING CONDITIONSTHEREBY PRODUCING THE CORRESPONDING BISNORALLOCHOLAN-22-AL-11-ONECOMPOUND, ACYLATING THE C-22 ALDEHYDE GROUP OF THE LATTER COMPOUND WITHAN ACYLATING AGENT IN THE PRESENCE OF AN ALKALI METAL SALT HAVING THESAME ACID RADICL AS SAID ACYLATING AGENT AND ACTING AS A CATALYST,THEREBY FORMING THE CORRESPONDING $22(22)-BISNORALLOCHOLENE-11-ONE-22-OL22-ACYLATE, OZONIZING SAID ACYLATE, AND HYDROLYZING THE RESULTINGOZONIDE UNDER REDUCING CONDITIONS, THEREBY FORMNG THE CORRESPONDINGALLLOPREGNANE-11,20-DIONE COMPOUND.